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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Acta+Neuropathol
2015 ; 130
(5
): 643-60
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Functional recovery in new mouse models of ALS/FTLD after clearance of
pathological cytoplasmic TDP-43
#MMPMID26197969
Walker AK
; Spiller KJ
; Ge G
; Zheng A
; Xu Y
; Zhou M
; Tripathy K
; Kwong LK
; Trojanowski JQ
; Lee VM
Acta Neuropathol
2015[Nov]; 130
(5
): 643-60
PMID26197969
show ga
Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss
of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the
molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal
lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the
pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear,
due in part to a lack of valid mouse models. We therefore generated new mice with
doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a
defective nuclear localization signal (?NLS) under the control of the
neurofilament heavy chain promoter. Expression of hTDP-43?NLS in these
'regulatable NLS' (rNLS) mice resulted in the accumulation of insoluble,
phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous
nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor
neuron loss, and progressive motor impairments leading to death. Notably,
suppression of hTDP-43?NLS expression by return of Dox to rNLS mice after disease
onset caused a dramatic decrease in phosphorylated TDP-43 pathology, an increase
in nuclear mTDP-43 to control levels, and the prevention of further motor neuron
loss. rNLS mice back on Dox also showed a significant increase in muscle
innervation, a rescue of motor impairments, and a dramatic extension of lifespan.
Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of
pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP.
Importantly, even after neurodegeneration and onset of motor dysfunction, removal
of cytoplasmic TDP-43 and the concomitant return of nuclear TDP-43 led to neuron
preservation, muscle re-innervation and functional recovery.
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